Panigrahi Inusha, Didel Siyaram, Kirpal Harita, Bellampalli Ravishankara, Miyanath Shabna, Mullapudi Nandita, Rao Sudha
Dept of Pediatrics, PGIMER, Chandigarh, India.
Dept of Pediatrics, PGIMER, Chandigarh, India.
Eur J Med Genet. 2018 Jul;61(7):369-371. doi: 10.1016/j.ejmg.2018.01.017. Epub 2018 Feb 23.
Osteogenesis imperfecta (OI) is an inherited disorder with osteoporosis and recurrent fractures. Children presenting with recurrent fractures and bowing of limbs have severe form of the disorder. Patients carrying homozygous WNT1 mutations have more frequent fractures while heterozygous carriers of the mutation in WNT1 gene are also found to have early onset osteoporosis. We identified a family with novel WNT1 mutation. The index case, a 6 month old child presented with fractures from early infancy. Next generation sequencing (NGS)done for the child didn't show any variations in other OI genes including COL1A1, COL1A2, SERPINH1, CRTAP, LEPRE1, PP1B, 1F1TM5 and BMP1 genes. Sanger sequencing showed 41bp deletion in splice region following exon 1 of WNT1 gene in homozygous state. The mutation was found to be likely pathogenic on bioinformatic analysis. To further characterize the significance of the mutation we studied his mother who is 30 year old with blue sclera and history of backache but no fractures. Her DXA scan of lumber spine showed osteoporosis and she was heterozygous for the mutation. The child's DXA scan showed T-score of -6.4 at lumbar spine level. Father also has history of backache and was carrier for the same deletion variant. The child was given 3 doses of zoledronate and did not have any further fractures. Thus, we conclude that this novel variant identified in the child with OI is likely cause for the disease and possibly zoledronate has a role in prevention of fractures in this case.
成骨不全症（OI）是一种伴有骨质疏松症和反复骨折的遗传性疾病。出现反复骨折和肢体弯曲的儿童患有该疾病的严重形式。携带纯合WNT1突变的患者骨折更为频繁，而WNT1基因突变的杂合携带者也被发现患有早发性骨质疏松症。我们鉴定了一个携带新型WNT1突变的家系。索引病例是一名6个月大的儿童，自婴儿早期就出现骨折。对该儿童进行的下一代测序（NGS）未显示其他OI基因（包括COL1A1、COL1A2、SERPINH1、CRTAP、LEPRE1、PP1B、1F1TM5和BMP1基因）有任何变异。桑格测序显示WNT1基因第1外显子后的剪接区域存在纯合状态的41bp缺失。经生物信息学分析，该突变可能具有致病性。为了进一步明确该突变的意义，我们研究了他30岁的母亲，她有蓝色巩膜和背痛史，但无骨折。她的腰椎双能X线吸收法（DXA）扫描显示骨质疏松，且为该突变的杂合子。该儿童的DXA扫描显示腰椎水平的T值为-6.4。父亲也有背痛史，是相同缺失变异的携带者。该儿童接受了3剂唑来膦酸治疗，此后未再发生骨折。因此，我们得出结论，在患有OI的儿童中鉴定出的这种新型变异可能是该疾病的病因，在这种情况下唑来膦酸可能对预防骨折有作用。
